Leptospirosis is a worldwide zoonotic disease that is caused by spirochetes in the genus Leptospira. This disease is now regarded as one of the important emerging infectious diseases worldwide, with the latest outbreaks occurring in Nicaragua, Brazil, India, Malaysia, Thailand and the United States. The clinical manifestations of leptospirosis are varied, ranging from a relatively mild flu-like illness to a severe syndrome of multi-organ infection that is associated with a high mortality. The ultimate goal of the proposed research is to increase our understanding of the basic biology and genetic differences between pathogenic and nonpathogenic strains of Leptospira, employing a range of genome based technologies. The specific hypothesis behind this proposal is that strains of Leptospira have major genetic differences that may be associated with their ability to cause disease, and that the pathogenic species alter the expression of appropriate genes in order to cope with the changes encountered in the environment. As such, we aim to increase our understaning of species diversity of different strains of Leptospira employing comparative genome hybridization techniques, and to understand the regulatory network(s) controlling gene expression that allow Leptospira species to sense and adapt to growth as either a parasitic or free-living organism. The Specific Aims are also designed to study the interaction between Leptospira and its host by monitoring the genomewide changes in leptospiral gene expression upon contact with host cells and to identify and characterize genes that are differentially expressed during host-pathogen interaction. An increased understanding of Leptospira biology will present opportunities to develop methods to address this pathogen, and will also serve as a model to understand the basic biology and pathogenic potential of emerging pathogenic species.